Matt Hoffman

, September 12–16, 2020, included findings from a survey conducted by Indu Subramanian, MD, and colleagues that shed light on the impact of loneliness as a predictor of disease severity in patients with Parkinson disease.

All told, the data identified that being lonely or socially isolated can be extraordinarily detrimental for patients and their well-being. Subramanian, who is the director of the VA Southwest Parkinson’s Disease Research, Education, and Clinical Centers and a member of the faculty at UCLA, noted that patients with reports of feeling lonely had higher PRO-PD scores, even more so than those who smoked and had high stress levels.

To learn more about the importance of patient-focused measures, especially amid the ongoing global pandemic, 

: What were the main takeaways from this survey?

 We have this way of measuring quality of life called the PRO-PD scale. Laurie Mischley, ND, PhD, who's a collaborator of mine, looked at the scale and it seems to be validated against our normal measures of quality of life. It's quite a patient-centered quality of life scale, actually, because it includes a number of things that the NIH had wanted to be included in patient-centered outcomes. So much of the research that we do and spend a lot of time talking about is actually completely not patient-centered.

What we showed is actually something like tremor, which is like the most obvious Parkinson disease symptom, and when you think about a patient with Parkinson, you think about someone who is maybe stooped over with a tremor. That actually doesn't have much to do with quality of life. But if you have a lot of friends, it can actually improve your quality of life significantly. And if you don't have any real relationships, it can actually be very, very bad for your quality of life. It really impacts a lot of the nonmotor issues that we talk about with Parkinson patients. Things like depression and anxiety, insomnia, apathy, those things are actually tremendously impacted by this issue of being socially isolated. That can be very powerful for a patient with Parkinson. That really can determine how they're doing on a day-to-day basis much more than anything we measure in a clinic with a physical exam or some of the scoring that we do traditionally.

How important is it to have a more patient-centered approach to care?

I think it's quite important to care about what patients care about and be more patient-centered. I think that not only do we identify this with our survey, but we also have come up with possible solutions to help it, which is exciting because so much of what we're talking about with COVID-19 is this doom and gloom, and I kind of frame it in the framework of the fact that Parkinson in and of itself is a pandemic. There's been a doubling of Parkinson patient cases in the last 40 years or so, and they say that by 2040, it will double again. We have a huge number of an expanding population of patients, and we haven't fully figured out why that is. Then, we have this loneliness pandemic, which honestly affects every person on the planet, it doesn't matter who you are, if you're rich or poor, or whatever. I mean, that is a pandemic that has kind of been a silent killer in some ways, and then we have this third pandemic that's influencing these other 2—the COVID-19 pandemic—which is really limiting our ability to see our patients and make dramatic changes with their pills, and we're just trying to keep our patients safe.

What are those interventions that can help?

We have some powerful possibilities to intervene. What we were titling social prescribing, which is a concept that has been established out there, but it's not very well known about. This is a concept of literally prescribing a social intervention or social connection to our patients. So. I can say, “Mr. Smith, I know that you're lonely and you don't have anyone who cares about you.”

We have this actually new VA intervention, where there were a number of volunteers that used to come physically into the VA—anyone's ever been to the VA, you probably have been greeted by a volunteer in the lobby—and those folks are being told to stay home to keep them safe. Some of them are family members of veterans, or the widows of veterans, and that's their identity, helping other veterans. And now we've told them to stay put in their homes for the last 6 months. There's this new intervention called the Compassionate Contact Corps, and they're matching these volunteers with veterans through a survey, seeing if they were in the same branch of the military, what their favorite movie is, their favorite hobbies, et cetera, and connecting people, hopefully with like interests. Then, these volunteers will actually be either doing a digital sort of meeting, if they can get our patients to participate with that type of technology.

We're also actually proactively calling people on the phone, which is really exciting. Just a simple phone call can actually make a huge amount of difference for somebody. There's actually been some data on the benefits for the volunteers as well, which is pretty exciting. So we’re actually helping with designing a few questions to put into that survey and seeing if that changes as people are working with each other and helping each other out. I'm quite excited because veterans who get lonely are actually at much higher risk of depression and anxiety. Suicide actually is really high in this population and then also so is substance abuse. We really have to be careful with these populations and be proactive and make sure that we're taking care of them.

But the intervention that I mentioned is actually a VA-specific intervention of social prescribing, but there have actually been other models of that, including one that the National Health System just wrote about in the 

. But they are doing it using link workers to connect isolated people with social interventions. It's a known kind of a thing that is being written about.

Who was involved in the survey population?

The actual survey that we did, even though I work at a VA, included thousands of patients from the general PD population, and there's a lot of women actually that were in the survey and younger women who were not that advanced. So, it's not the standard veteran population that I see day to day. I do work with research and all areas of this sort of interface of integrative medicine and I people tend to come to me because I am a boarded neurologist with a movement sort of background that has a yoga teacher training, as well as an integrative medicine background, which I don't think there really are very many of—maybe one other person on the planet—so I ended up working and collaborating with people.

Are there any distinct differences between the general Parkinson population and veterans with Parkinson disease?

Veterans in general are definitely, at baseline, a tougher population. They tend to be stoics. Then, there's a stigma associated with loneliness, so you actually have to come in and talk to people about it. Sometimes people think if they have a mental health issue, there's a huge stigma. Men are much less likely to identify with this problem and be honest about it, and that's my main VA population. So, I think just normalizing it and saying that this happens to all of us is helpful.

How important do you feel it is to recognize loneliness, particularly in the midst of a global pandemic?

I gave a talk like this the other day and had a colleague actually in a different part of the country write an email and reach out to me because they were lonely and battling a lot of these sorts of issues with feeling not in control of their emotions and things around that. I think this is something that we as a community need to realize affects all of us. That any one of us could become lonely. You could be happily married and still be lonely, so it's really out there, and it is something that we have to proactively identify. There's possibly a neighbor that lives on your street that could have this, be battling this, and just a simple phone call or dropping off something—a nice card for them, saying thinking about you, or something—can help. I think we're all socially connected as a basic human need.

I was really impressed with the data that you know, loneliness is, can impact actually sleep, it can impact our thoughts. If we get so lonely, it actually makes us hyper-vigilant and start thinking about the world in a very paranoid kind of way where we’ll fixate on all the negative stuff. I actually have a colleague with who I am writing something with currently, he's a doctor in Barcelona. In their lockdown, the patients weren't allowed to go out of even their little apartments to go outside. These patients became so lonely and sensory deprived that they all they got was some news once in a while, and they actually started getting psychotic and really anxious and depressed. It really changed their mental state. I think it is it's almost like being in solitary confinement sometimes. We've somehow created some of these situations for our patients in hopes to keep them safe right now, so I think we just have to be really mindful of that.

I think a lot of even my colleagues are just going through a lot in and of themselves with burning out, they're working nonstop on these Zoom meetings with really not a lot of true connection with each other. Part of the beauty of working together in medicine is the teamwork and the checking in with each other and knowing about how your team is doing. I lead a team and so much of what I do is just making sure that we're all doing okay, and that's not easy to do when you’re wearing PPE with masks and a face shield all day long. I can't hug my patients or colleagues and it's a very disconnected way that we're interacting, honestly. It's been, it's been very tough.

I will say I'm hosting a number of my colleagues on a virtual support group for patients, and it's been really nice to see them actually through this type of modality. We kind of get off the line and are like “I miss you; I haven't seen you in 6 months!” Normally, we would have seen each other 3 times at different meetings, and it's just a very different way that we're interacting with even our medical colleagues and health care providers right now. I think we just have to be mindful and vigilant, even in our own selves and with our close colleagues, and just make that extra phone call to check-in or schedule a virtual happy hour with somebody that you know that has just been working nonstop and hasn't had a break. If you to give them a hug—even if it's virtually—I think can be really, really helpful to just share the common human experience of what we're all going through right now.

REFERENCE
Subramanian I, Mischley L, Farahnik J. Loneliness/Social Isolation as a Risk Factor for Worsened Parkinson Disease Severity. Presented at MDS Virtual Congress; September 12–16, 2020.

Articles

The director of the VA Southwest Parkinson’s Disease Research, Education, and Clinical Centers spoke to the importance of patient-focused interventions in PD.

The Importance of Patient-Centered Care in Parkinson Disease

Preliminary phase 1 safety data (NCT03283826) on the investigational off-the-shelf, allogeneic Epstein-Barr virus (EBV)-targeted T-cell therapy ATA188 (Atara Biotherapeutics) suggest that the agent is well tolerated in adult individuals with progressive forms of multiple sclerosis (MS).

The data include those patients dosed up to April 2020 (n = 25), each of which received ≥1 dose of ATA188. Ultimately, there were no events worse than grade 3 reported. In total, 2 treatment-emergent serious adverse events (AEs) were noted: a grade 2 incidence of muscle spasticity, which was not related to therapy, and a grade 3 incidence of MS relapse, which was considered possibly related to treatment.

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020, by Amit Bar-Or, MD, the Melissa and Paul Anderson President's Distinguished Professor of Neurology, Perelman School of Medicine, University of Pennsylvania.

“It was very well-tolerated, and the good news is that we are not seeing that even with the longer-term dosing of patients with these cells going out to 21 months, 24 months, we're not seeing augmentation of safety issues,” Jakob Dupont, MD, executive vice president, and head of global research and development, Atara Biotherapeutics, told 

. “One of the aspects of ATA188 is that it's a very specific treatment. These T cells are really directed against only EBV-expressing infected cells, and so we don't have a lot of off-target toxicity because of that.”

Progressive and Relapsing-Remitting Multiple Sclerosis Share Similar Fatigue Severity

As well as the generally low-grade AEs that were observed, there were no dose-limiting toxicities, cytokine release syndrome, graft-versus-host disease, or infusion reactions reported. “With a lot of cell therapies, whether it's CAR-T or whatever it may be, you can see neurological symptoms, you can see cytokine release syndrome and so forth, and we really don't see those types of effects with our treatment because, again, the specificity of our EBV T cells. They're not directed against the patient's own self-antigens, if you will,” Dupont noted.

The first part of this included 4 cohorts of patients who received escalating doses to determine the recommended dose for the second part of the study. The participants were followed for 1 year, and then given the option to participate in a 4-year open-label extension (OLE) at the recommended dose, which was determined by Cohort 3.

In addition to the safety measures, sustained disability improvement (SDI)—defined as improvement in Expanded Disability Status Scale (EDSS) or Timed 25-Foot Walk (T25FW) at 2 or more consecutive time points—was assessed, as well as Fatigue Severity Scale (FSS), 12-item MS Walking Scale (MSWS-12), MS Impact Scale-29 (physical; MSIS-29), and whole-brain volume. The efficacy end points were assessed in all 4 cohorts (n = 24) at the 6-month mark, and in the first 3 cohorts (n = 17) at 12 months.

A higher proportion of patients who were treated with ATA188 showed sustained disability improvement (SDI) with an increasing dose. At 6 months, 6 patients met SDI criteria, and at 12 months, 5 patients did so. This was driven by EDSS score in all but 2 patients at both time points. In cohorts 1, 2, and 3, every patient with SDI at the 6-month time point maintained that status through 12 months.

Additionally, those who achieved SDI at any time point maintained it at all future time points and tended to show improvements in fatigue, physical function, and MRI whole brain volume at 1 year. As of June 2020, OLE data from the 15-month time point were available for 4 individuals: 3 had SDI at 6 and 12 months that was maintained to that point.

“We are encouraged by what we’re seeing in the clinical trial because when we get into Cohort 3, we are seeing sustained disability improvement in these patients…this isn’t just 1 point in time where we’re seeing a patient doing better today,” Dupont said.

REFERENCE
Pender M, Hodgkinson S, Broadley S. Phase I study of ATA188, an off-the-shelf, allogeneic Epstein-Barr virus-targeted T-cell immunotherapy for progressive forms of multiple sclerosis. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0226.

Atara Biotherapeutics’ allogeneic EBV-targeted T-cell therapy, ATA188, is well-tolerated in phase 1, with a dose identified for the randomized placebo-controlled portion of the study.

Investigational Drug Targeting Epstein-Barr Virus Shows Promise for Progressive MS

Marinus Pharmaceuticals has announced positive top-line results of its registrational phase 3 MARIGOLD clinical trial (NCT03572933) of 

 in the treatment of children and young adults with CDKL5 deficiency disorder (CDD), a rare, genetic epilepsy accompanied by refractory seizures.

All told, those treated with the positive allosteric GABAA receptor modulator showed a significant median reduction of 32.2% in 28-day major motor seizure frequency in comparison to a 4.0% reduction for those in the placebo group, which achieved the primary end point (

 = .002). Marinus is planning to present the top-line results at an upcoming scientific meeting.

“The MARIGOLD Study has 2 important firsts. It’s the first double-blind placebo-controlled study providing evidence of efficacy specific to CDD and the first phase 3 trial to examine 3 times a day dosing of ganaxolone in pediatric patients,” said Scott Braunstein, MD, chief executive officer, Marinus Pharmaceuticals, in a statement. “We believe we are 1 step closer to providing the first treatment indicated for CDD, and plan to continue our investments in the oral ganaxolone franchise.”

Based on these results, the company noted it anticipates submitting a new drug application(NDA) for ganaxolone in the treatment of CDD to the FDA in mid-2021 and a Marketing Authorization Application (MAA) for ganaxolone for the treatment of CDD to the EMA by the end of the third quart of 2021. Previously, Marinus 

received a rare pediatric disease designation from the FDA

 for ganaxolone for the treatment of CDD.

The MARIGOLD trial’s primary efficacy end point assessed the percentage change in 28-day frequency of major motor seizures during the double-blind phase relative to the prospective baseline period. The trial enrolled 101 children and young adults aged 2 to 21 years with a confirmed, disease-related CDKL5 gene variant. Following thee 6-week baseline period, trial participants were randomized to receive either oral ganaxolone (dosed up to 1800 mg per day) or placebo for 17 weeks, in addition to their existing anti-seizure treatment. Following the double-blind phase, patients were eligible to continue receiving ganaxolone in an open-label extension.

Optimizing Care Transition for Adolescents With Epilepsy

“CDD is a severe genetic epilepsy that can cause hundreds of seizures for patients each day,” Scott Demarest, MD, principal investigator, and assistant professor of pediatrics-neurology, University of Colorado, said in a statement. “Existing antiepileptic medications fail to produce an adequate and durable response in the majority of patients. The positive results from Marinus’ trial demonstrate that ganaxolone can provide significant seizure reduction in patients with CDD, an important advance for the CDD community.”

The trial data also revealed numerical trends in favor of ganaxolone across several predefined secondary end points, though the agent did not achieve statistical significance. Ganaxolone did, however, meet statistical significance in some exploratory secondary end points.

As for safety, ganaxolone was considered generally well-tolerated, with a safety profile consistent with has been observed in prior clinical studies. The most frequent adverse event (AE) reported was somnolence.

“Today’s success with ganaxolone in CDD will pave the way for us to accelerate our clinical studies in tuberous sclerosis complex and possibly other rare pediatric epilepsies as well,” said Joe Hulihan, MD, chief medical officer, Marinus Pharmaceuticals, said in a statment. “We will continue to explore the potential for ganaxolone’s unique mechanism of action to address other areas of unmet medical need.”

Marinus noted that it plans to launch an Expanded Access Program (EAP) in the fourth quarter of 2020, which will allow patients who were not able to participate in the clinical trial to begin receiving treatment with ganaxolone under a treatment protocol.

REFERENCE
Ganaxolone Achieves Primary Endpoint in Phase 3 Trial for CDKL5 Deficiency Disorder (CDD), a Rare Form of Genetic Epilepsy. News release. Radnor, PA. Marinus Pharmaceuticals. Published September 14, 2020. Accessed September 18, 2020. biospace.com/article/releases/ganaxolone-achieves-primary-endpoint-in-phase-3-trial-for-cdkl5-deficiency-disorder-cdd-a-rare-form-of-genetic-epilepsy

Marinus Pharmaceuticals’ positive allosteric GABAA receptor modulator ganaxolone was associated with significant median reductions in 28-day major motor seizure frequency compared to placebo.

Ganaxolone Meets Primary End Point in CDKL5 Deficiency Disorder Study

New results from the phase 3b CASTING study (NCT02861014) suggest that a wide range of disease-related and demographic subgroups of patients with multiple sclerosis (MS) who are treated with ocrelizumab (Ocrevus; Genentech) achieve high rates of no evidence of disease activity (NEDA) status after 2 years. This status was reached regardless of prior exposure to disease-modifying therapies (DMTs).

Additionally, a second dataset from CASTING revealed that individuals with relapsing MS who had a suboptimal response to prior treatment experienced symptom improvement after 2 years across the majority of domains measured by SymptoMScreen, a patient-reported outcome tool designed to rapidly assess symptom limitations across 12 symptoms commonly reported in MS. These gains were most pronounced for sensory, fatigue, and vision-related symptoms.

, the 8th Joint ECTRIMS-ACTRIMS meeting, September 11–13, 2020, the first set by Heinz Wiendl, MD, head, Weindl Lab, Clinic for Neurology, Institute for Translational Neurology, University Hospital Münster, and the second set by Ilya Kister, MD, associate professor, Department of Neurology, NYU Grossman School of Medicine, and director, Neuromyelitis Optica Treatment and Research Program, NYU Langone Health.

Wiendl and colleagues’ data included 680 patients with a baseline Expanded Disability Status Scale (EDSS) score of 2.1 (standard deviation [SD], 1.1), of which 411 (60.4%) had been treated with 1 prior oral or injectable DMT and 269 (39.6%) had been treated with 2 prior DMTs. MRI-only disease activity was the reason for enrollment for 167 patients (24.6%) while 238 (35%) had only relapse, and 275 (40.4%) had both.

After the 2-year treatment period, 492 of 658 patients (74.8%) qualified for NEDA status (with MRI re-baselined at Week 8 of treatment). The highest rates of NEDA were observed in those who were enrolled due to only MRI activity (80.6%). Those with only relapses had NEDA at a rate of 75.1% and those with both had a rate of 70.5%.

Ozanimod Shows Long-Term Safety, Efficacy in Open-Label Extension

NEDA rates did not vary by age at baseline when patients were stratified by those aged 40 years and younger (74.7%) and those older than 40 years (75%).

Additionally, the NEDA rates across disease-related subgroups were the highest in the subgroups of those with baseline EDSS score <2.5 (77.2%), those with ≤1 relapse prior to enrollment (78.2%), and the event leading to enrollment occurring ≥6 months prior to study entry (75.8%). These groups were highest compared to their counterpart subgroups of those with EDSS scores of ≥2.5 (70.8%), with >1 relapse prior to enrollment (66.3%), and with the event leading to enrollment occurring <6 months prior to entry (71.0%).

Those who received 1 prior DMT experienced higher rates of NEDA (77.6%) than those with 2 prior DMTs (70.3%), and the rates remained generally high when stratified by the last prior DMT received before enrollment—interferons, 81.1%; glatiramer acetate, 73.9%; dimethyl fumarate, 73.8%; teriflunomide 69.8%; fingolimod, 68.9%.

Meanwhile, the dataset presented by Kister et al. included the same cohort of patients to evaluate SymptoMScreen. Each domain of the tool is scored on a 7-point Likert scale, ranging from 0 (not affected) to 6([total limitation), and domain scores are summed to calculate a total score ranging from 0 to 72. SymptoMScreen was performed at baseline, Week 48 (which made up the 1-year interim data) and Week 96 (which made up the 2-year final data).

Their findings showed that the total SymptoMScreen mean score reflected mild symptom burden at baseline (15.19 [SD, 12.67]) and improved significantly through the second year (13.62 [SD, 12.51]; 

 <.001). As mentioned, there were significant improvements reported by patients for sensory symptoms (Δ-0.28; 

 <.001). Additionally, there were marked gains in symptoms of depression (Δ-0.15; 

As well, the proportion of patients with ≥1 symptom causing at least moderate limitation (defined as a domain score ≥4) decreased from 31.6% at baseline to 26.3% at Year 2.

Non-significant improvements in symptom burden after 2 years were reported in the domains of walking (Δ-0.1), cognition (Δ-0.10), anxiety (Δ-0.07), bodily pain (Δ-0.05), hand function (Δ-0.03), and bladder control (Δ-0.01). There was a non-significant worsening was observed in the spasticity domain (Δ+0.04).

REFERENCES
1. Wiendl H, Comi G, Oreja-Guevara C, et al. Ocrelizumab Phase IIIb efficacy from CASTING: 2-year NEDA (MRI re-baselined) subgroup rates in RRMS patients with a suboptimal response to prior DMTs. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P0219.
2. Kister I, Cutter G, Buffels R, Clinch S, Kuenzel T, Vermersch P. Improvements in patient-reported SymptoMScreen scores among ocrelizumab-treated patients with RRMS: 2-year results from the CASTING clinical trial. Presented at MS Virtual 2020 Joint ECTRIMS-ACTRIMS meeting; September 11–13, 2020. Abstract P1039.

A pair of datasets from the phase 3b CASTING study of ocrelizumab (Ocrevus; Genentech) suggest that patients treated with the agent experienced high rates of no evidence of disease activity status regardless of prior DMT exposure.

Author | Matt Hoffman

Articles

The Importance of Patient-Centered Care in Parkinson Disease

Investigational Drug Targeting Epstein-Barr Virus Shows Promise for Progressive MS

Ganaxolone Meets Primary End Point in CDKL5 Deficiency Disorder Study

Ocrelizumab Treatment Results in High NEDA Rates, Improvements in MS Symptoms